Phenyl derivatives useful as tachykinin antagonists

ABSTRACT

Compounds of formula (I), or a salt or prodrug thereof are tachykinin antagonists.

This invention relates to a class of aromatic compounds which are usefulas tachykinin antagonists. More particularly, the compounds of theinvention contain a phenyl moiety and hydroxyl or ether moiety.

The tachykinins are a group of naturally occurring peptides found widelydistributed throughout mammalian tissues, both within the centralnervous system and in peripheral nervous and circulatory systems.

The structures of three known mammalian tachykinins are as follows:Substance P:

Arg-Pro-Lys-Pro-Gln-Gln-Phe-Phe-Gly-Leu-Met-NH₂

Neurokinin A:

His-Lys-Thr-Asp-Ser-Phe-Val-Gly-Leu-Met-NH₂

Neurokinin B:

Asp-Met-His-Asp-Phe-Phe-Val-Gly-Leu-Met-NH₂

For example, substance P is believed inter alia to be involved in theneurotransmission of pain sensations [Otsuka et al, "Role of Substance Pas a Sensory Transmitter in Spinal Cord and Sympathetic Ganglia" in 1982Substance P in the Nervous System, Ciba Foundation Symposium 91, 13-34(published by Pitman) and Otsuka and Yanagisawa, "Does Substance P Actas a Pain Transmitter?" TIPS (Dec. 1987) 8 506-510], specifically in thetransmission of pain in migraine (B. E. B. Sandberg et al, J. Med Chem,(1982) 25 1009) and in arthritis [Levine et al in Science (1984) 226547-549]. These peptides have also been implicated in gastrointestinal(GI) disorders and diseases of the GI tract such as inflammatory boweldisease [Mantyh et al in Neuroscience (1988) 25 (3) 817-37 and D. Regoliin "Trends in Cluster Headache" Ed. Sicuteri et al Elsevier ScientificPublishers, Amsterdam (1987) page 85)]. It is also hypothesised thatthere is a neurogenic mechanism for arthritis in which substance P mayplay a role [Kidd et al "A Neurogenic Mechanism for SymmetricalArthritis" in The Lancet, Nov. 11, 1989 and Gronblad et al"Neuropeptides in Synovium of Patients with Rheumatoid Arthritis andOsteoarthritis" in J. Rheumatol. (1988) 15(12) 1807-10]. Therefore,substance P is believed to be involved in the inflammatory response indiseases such as rheumatoid arthritis and osteoarthritis, and fibrositis[O'Byrne et al in Arthritis and Rheumatism (1990) 33 1023-8]. Otherdisease areas where tachykinin antagonists are believed to be useful areallergic conditions [Hamelet et al Can. J. Pharmacol. Physiol. (1988) 661361-7], immunoregulation [Lotz et al Science (1988) 241 1218-21 andKimball et al, J. Immunol. (1988) 141 (10) 3564-9] vasodilation,bronchospasm, reflex or neuronal control of the viscera [Mantyh et al,PNAS (1988) 85 3235-9] and, possibly by arresting or slowingβ-amyloid-mediated neurodegenerative changes [Yankner et al Science(1990) 250, 279-82] in senile dementia of the Alzheimer type,Alzheimer's disease and Downs Syndrome. Substance P may also play a rolein demyelinating diseases such as multiple sclerosis and amyotrophiclateral sclerosis [J. Luber-Narod et. al., poster to be presented at C.I. N. P. XVIIIth Congress, 28th June-2nd July, 1992, in press], and indisorders of bladder function such as bladder detrusor hyper-reftexia(Lancet, 16th May, 1992, 1239).

It has furthermore been suggested that tachykinins have utility in thefollowing disorders: depression, dysthymic disorders, chronicobstructive airways disease, hypersensitivity disorders such as poisonivy, vasospastic diseases such as angina and Reynauld's disease,fibrosing and collagen diseases such as scleroderma and eosinophillicfascioliasis, reflex sympathetic dystrophy such as shoulder/handsyndrome, addiction disorders such as alcoholism, stress related somaticdisorders, neuropathy, neuralgia, disorders related to immuneenhancement or suppression such as systemic lupus erythmatosis (Europeanpatent application no. 0 436 334), opthalmic disease such asconjuctivitis, vernal conjunctivitis, and the like, and cutaneousdiseases such as contact dermatitis, atropic dermatitis, urticaria, andother eczematoid dermatitis (European patent application no. 0 394 989).

We have now found a class of non-peptides which are potent antagonistsof tachykinin.

The present invention provides a compound of formula (I), or a salt orprodrug thereof: ##STR2## wherein

R¹ represents a nitrogen containing aromatic or non-aromatic heterocycleoptionally substituted by one or more groups selected from C₁₋₆ alkyl,C₁₋₆ alkoxy, oxo, thioxo, halo, trifluoromethyl, nitro, NR^(a) R^(b),NR^(a) COR^(b), CONR^(a) R^(b), CO₂ R^(a), SO₂ R^(a) and CH₂ OR^(a),where R^(a) and R^(b) each independently represent H, C₁₋₆ alkyl orphenyl optionally substituted by C₁₋₆ alkyl, halo or trifluoromethyl;

R² represents H, C₁₋₆ alkyl or C₂₋₆ alkenyl;

R³ represents C₁₋₃ alkyl substituted by a phenyl group which may itselfoptionally be substituted by one or more of C₁₋₆ alkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, halo, cyano, nitro, trifluoromethyl, trimethylsilyl,SR^(c), SOR^(c), SO₂ R^(c), OR^(c), NR^(c) R^(d), NR^(c) COR^(d), NR^(c)COOR^(d), COOR^(c) and CONR^(c) R^(d) ;

R⁴ represents H, C₁₋₆ alkyl or C₂₋₆ alkenyl;

each R⁵ independently represents C₁₋₆ alkyl, C₁₋₆ alkoxy, halo ortrifluoromethyl;

Z represents 0 or S; and

m represents 0, 1, 2 or 3.

The alkyl, alkenyl and alkynyl groups referred to with respect to any ofthe formulae herein may represent straight, branched or cyclic groups orcombinations thereof. Thus, for example, suitable alkyl groups includemethyl, ethyl, n- or iso-propyl, n-, sec-, iso- or tert-butyl,cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl, and cycloalkyl-alkylgroups such as cyclopropylmethyl; suitable alkenyl groups include vinyland allyl; and suitable alkynyl groups include propargyl.

For phenylalkyl substituents, the alkyl moiety may be straight orbranched.

The term "halo" as used herein includes fluoro, chloro, bromo and iodo.

Aptly R¹ represents an optionally substituted aromatic heterocycle.

The nitrogen containing aromatic heterocycle represented by R¹ may be,for example, a 5- or 6-membered heterocycle and may contain, in additionto the nitrogen atom, one or more heteroatoms selected from O, S and N,or groups NR⁸ where R⁸ is H or C₁₋₆ alkyl.

Suitably R¹ represents an optionally substituted 5-membered heteroarylmoiety selected from pyrrolyl, triazolyl, tetrazolyl, thiazolyl,oxazolyl, oxadiazolyl, thiadiazolyl, isoxazolyl, isothiazolyl andimidazolyl. Preferably R¹ represents optionally substituted pyrrolyl orimidazolyl. More preferably R¹ represents imidazolyl substituted by anitro or an amino group.

Aptly R¹ represents an optionally substituted non-aromatic heterocycle.

Suitably R¹ represents a 4, 5, 6, 7 or 8 membered ring which may haveone heteroatom in addition to the nitrogen atom, for example an oxygenatom. Apt groups include those of the formula ##STR3## wherein Q is CH₂,NR⁸ where R⁸ is as hereinbefore defined, O or S, n¹ is 1, 2 or 3 and m¹is 1 or 2 with the proviso that when Q is NR⁸, O or S neither n¹ nor m¹is 1; which group can be optionally substituted by one or two oxo groupsor C₁₋₆ alkyl groups.

A favoured non-aromatic group R¹ is morpholino.

R¹ is linked to carbon atom which also bears the R² group and the othergroups shown in formula (I) via the nitrogen atom.

Suitable values for the groups R² and R⁴ include R and methyl,preferably H.

Suitably R³ represents a C₁₋₆ alkyl chain bearing a substituent which isa substituted phenyl group. Suitable phenyl substituents include methyl,methoxy, nitro, cyano, halo and trifluorometyl. Preferably R³ representsmethyl substituted by a substituted phenyl group. Preferably one or twosubstituents will be present in the phenyl ring. More preferably R³represents methyl substituted by 3,5-disubstituted phenyl, such as3,5-dimethylphenyl or 3,5-bistrifluoromethylphenyl.

Preferably m represents zero.

A preferred sub-class of compounds according to the invention isrepresented by formula (Ia): ##STR4## wherein

X is N or CH;

R²² and R²³ each independently represent H, C₁₋₆ alkyl, C₂₋₆ alkenyl,C₁₋₆ alkoxy, halo, cyano, nitro, trifluoromethyl, trimethylsilyl,hydroxy, phenoxy or amino;

R²⁴ is NO₂ or NH₂, and may be located at any available ring position;and salts and prodrugs thereof.

Specific compounds within the scope of the present invention include:

(+)-1-[3,5-(bistrifluoromethylphenyl)methyloxy]-2-N(2,5-dimethylpyrrole)-2-phenylethane;

1-[3,5-(bistrifluoromethylphenyl)methyloxy]-2-N(imidazole)-2-phenylethane;

(±)-1-[3,5-(bistrifluoromethylphenyl)methyloxy]-2-N(2-nitroimidazole)-2-phenylethane;

(±)-2-N(2-aminoimidazole)-1-[3,5-(bistrifluoromethylphenyl)methyloxy]-2-phenylethane;

(±)-1-[3,5-(bistrifluoromethylphenyl)methyloxy]-2-N(4-nitroimidazole)-2-phenylethane;

(±)-1-[3,5-(bistrifluoromethylphenyl)methyloxy]2-N-morpholino-2-phenylethane;

(±)-1-[3,5-(bistrifluoromethylphenyl)methyloxy]2-N-(piperidine-2,6-clione-2-phenylethaneand salts and prodrugs thereof especially the pharmaceuticallyacceptable salts-thereof.

For use in medicine, the salts of the compounds of formula (I) will benon-toxic pharmaceutically acceptable salts. Other salts may, however,be useful in the preparation of the compounds according to the inventionor of their non-toxic pharmaceutically acceptable salts. Suitablepharmaceutically acceptable salts of the compounds of this inventioninclude acid addition salts which may, for example, be formed by mixinga solution of the compound according to the invention with a solution ofa pharmaceutically acceptable acid such as hydrochloric acid, fumaricacid, p-toluenesulphonic acid, maleic acid, succinic acid, acetic acid,citric acid, tartaric acid, carbonic acid or phosphoric acid. Salts ofamine groups may also comprise quaternary ammonium salts in which theamino nitrogen atom carries a suitable organic group such as an alkyl,alkenyl, alkynyl or aralkyl moiety. Furthermore, where the compounds ofthe invention carry an acidic moiety, suitable pharmaceuticallyacceptable salts thereof may include metal salts such as alkali metalsalts, e.g. sodium or potassium salts; and alkaline earth metal salts,e.g. calcium or magnesium salts.

The present invention includes within its scope prodrugs of thecompounds of formula (I) above. In general, such prodrugs will befunctional derivatives of the compounds of formula (I) which are readilyconvertible in vivo into the required compound of formula (I).Conventional procedures for the selection and preparation of suitableprodrug derivatives are described, for example, in "Design of Prodrugs",ed. H. Bundgaard, Elsevier, 1985.

The present invention includes within its scope solyates of thecompounds of formula (I) and, salts thereof, for example, hydrates.

The compounds according to the invention have at least one asymmetriccentre, and may accordingly exist both as enantiomers and asdiastereoisomers. It is to be understood that all such isomers andmixtures thereof are encompassed within the scope of the presentinvention.

The present invention further provides pharmaceutical compositionscomprising one or more compounds of formula (I) in association with apharmaceutically acceptable carrier.

Preferably the compositions according to the invention are in unitdosage forms such as tablets, pills, capsules, powders, granules,solutions or suspensions, or suppositories, for oral, parenteral orrectal administration, or administration by inhalation or insufflation.

For preparing solid compositions such as tablets, the principal activeingredient is mixed with a pharmaceutical carrier, e.g. conventionaltableting ingredients such as corn starch, lactose, sucrose, sorbitol,talc, stearic acid, magnesium stearate, dicalcium phosphate or gums, andother pharmaceutical diluents, e.g. water, to form a solidpreformulation composition containing a homogeneous mixture of acompound of the present invention, or a non-toxic pharmaceuticallyacceptable salt thereof. When referring to these preformulationcompositions as homogeneous, it is meant that the active ingredient isdispersed evenly throughout the composition so that the composition maybe readily subdivided into equally effective unit dosage forms such astablets, pills and capsules. This solid preformulation composition isthen subdivided into unit dosage forms of the type described abovecontaining from 0.1 to about 500 mg of the active ingredient of thepresent invention. The tablets or pills of the novel composition can becoated or otherwise compounded to provide a dosage form affording theadvantage of prolonged action. For example, the tablet or pill cancomprise an inner dosage and an outer dosage component, the latter beingin the form of an envelope over the former. The two components can beseparated by an enteric layer which serves to resist disintegration inthe stomach and permits the inner component to pass intact into theduodenum or to be delayed in release. A variety of materials can be usedfor such enteric layers or coatings, such materials including a numberof polymeric acids and mixtures of polymeric acids with such materialsas shellac, cetyl alcohol and cellulose acetate.

The liquid forms in which the novel compositions of the presentinvention may be incorporated for administration orally or by injectioninclude aqueous solutions, suitably flavoured syrups, aqueous or oilsuspensions, and flavoured emulsions with edible oils such as cottonseedoil, sesame oil, coconut oil or peanut oil, as well as elixirs andsimilar pharmaceutical vehicles. Suitable dispersing or suspendingagents for aqueous suspensions include synthetic and natural gums suchas tragacanth, acacia, alginate, dextran, sodium carboxymethylcellulose,methylcellulose, polyvinylpyrrolidone or gelatin.

Compositions for inhalation or insufflation include solutions andsuspensions in pharmaceutically acceptable, aqueous or organic solvents,or mixtures thereof, and powders. The liquid or solid compositions maycontain suitable pharmaceutically acceptable excipients as set outabove. Preferably the compositions are administered by the oral or nasalrespiratory route for local or systemic effect. Compositions inpreferably sterile pharmaceutically acceptable solvents may be nebulisedby use of inert gases. Nebulised solutions may be breathed directly fromthe nebulising device or the nebulising device may be attached to a facemask, tent or intermittent positive pressure breathing machine.Solution, suspension or powder compositions may be administered,preferably orally or nasally, from devices which deliver the formulationin an appropriate manner.

The present invention further provides a process for the preparation ofa pharmaceutical composition comprising a compound of formula (I), whichprocess comprises bringing a compound of formula (I) into associationwith a pharmaceutically acceptable carrier or excipient.

The compounds of formula (I) are of value in the treatment of a widevariety of clinical conditions which are characterised by the presenceof an excess of tachykinin, in particular substance P, activity. Thesemay include disorders of the central nervous-system such as anxiety,depression, psychosis and schizophrenia; neurodegenerative disorderssuch as dementia, including senile dementia of the Alzheimer type,Alzheimer's disease and Down's syndrome; demyelinating diseases such asMS and ALS and other neuropathological disorders such as peripheralneuropathy, for example diabetic and chemotherapy-induced neuropathy,and postherpetic and other neuralgias; respiratory diseases,particularly those associated with excess mucus secretion such aschronic obstructive airways disease, bronchopneumonia, chronicbronchitis, cystic fibrosis and asthma, and bronchospasm; inflammatorydiseases such as inflammatory bowel disease, psoriasis, fibrositis,osteoarthritis and rheumatoid arthritis; allergies such as eczema andrhinitis; hypersensitivity disorders such as poison ivy; ophthalmicdiseases such as conjunctivitis, vernal conjunctivitis, and the like;cutaneous diseases such as contact dermatitis, atropic dermatitis,urticaria, and other eczematoid dermatitis; addiction disorders such asalcoholism; stress related somatic disorders; reflex sympatheticdystrophy such as shoulder/hand syndrome; dysthymic disorders; adverseimmunological reactions such as rejection of transplanted tissues anddisorders related to immune enhancement or suppression such as systemiclupus erythematosis; gastrointestinal (GI) disorders and diseases of theGI tract such as disorders associated with the neuronal control ofviscera such as ulcerative colitis, Crohn's disease and incontinence;disorders of bladder function such as bladder detrusor hyper-reflexia;fibrosing and collagen diseases such as scleroderma and eosinophilicfascioliasis; disorders of blood flow caused by vasodilation andvasospastic diseases such as angina, migraine and Reynaud's disease; andpain or nociception, for example, that attributable to or associatedwith any of the foregoing conditions, especially the transmission ofpain in migraine.

The compounds of formula (I) are particularly useful in the treatment ofpain or nociception and/or inflammation and disorders associatedtherewith such as, for example, neuropathy, such as diabetic andchemotherapy-induced neuropathy, postherpetic and other neuralgias,asthma, osteroarthritis, rheumatoid arthritis and especially migraine.

The present invention further provides a compound of formula (I) for usein therapy. According to a further or alternative aspect, the presentinvention provides a compound of formula (I) for use in the manufactureof a medicament for the treatment of physiological disordersassociated-with an excess of tachykinins, especially substance P. Thepresent invention also provides a method for the the treatment orprevention of physiological disorders associated with an excess oftachykinins, especially substance P, which method comprisesadministration to a patient in need thereof of a tachykinin reducingamount of a compound of formula (I) or a composition comprising acompound of formula (I).

In the treatment of the conditions associated with an excess oftachykinins, a suitable dosage level is about 0.001 to 50 mg/kg per day,in particular about 0.01 to about 25 mg/kg, such as from about 0.05 toabout 10 mg/kg per day. For example, in the treatment of conditionsinvolving the neurotransmission of pain sensations, a suitable dosagelevel is about 0.001 to 25 mg/kg per day, preferably about 0.005 to 10mg/kg per day, and especially about 0.005 to 5 mg/kg per day. Thecompounds may be administered on a regimen of 1 to 4 times per day,preferably once or twice per day.

The compounds according to the invention may be prepared from compoundsof formula (II) ##STR5## wherein R², R³, R⁴, R⁵, Z and m are as definedfor formula (I) above and R³⁰ represents a leaving group, by reationwith a metallated aromatic heterocycle of formula R¹ -M wherein R¹ is asdefined for formula (I) and M represents a metal, such as an alkaimetal, for example sodium or lithium, or with an non-aromatic amine R¹-H, optionally in the presence of a tertiary amine base.

Suitable leaving groups represented by R³⁰ include aryl and alkylsulphonate groups, such as tosylate and mesylate groups.

The reaction is conveniently effected in a suitable organic solvent,such as dimethyl formamide, or an ether, such as, for example,tetrahydrofuran, or a mixture thereof, suitably at room temperature.

Alternatively, compounds of formula (I) may be prepared from compoundsof formula (III) ##STR6## wherein R², R³, R⁴, R⁵, Z and m are definedfor formula (I) using conventional methods for the construction of theheteroaromatic ring. Suitable methods are described, for example, inComprehensive Heterocyclic Chemistry, Katritzky and Rees, PergamonPress, 1984.

Compounds of formula (I) may also be prepared from other compounds offormula (I) by interconversion processes. Such processes areparticularly useful for modifying substituents in the heteroaromaticring. For example, compounds of formula (I) wherein R¹ represents aheteroaryl moiety substituted by an amino group may be prepared from thecorresponding compounds of formula (I) wherein R¹ represents the sameheteroaryl moiety substituted by a nitro group, by reduction. Furthersuitable interconversion procedures will be readily apparent to thoseskilled in the art.

Compounds of formula (II) may be prepared from intermediates of formula(IV) ##STR7## wherein R², R³, R⁴, R⁵, Z and m are as defined for formula(I), by conversion of the hydroxy group to a leaving group underconventional conditions, for example, by reaction with a compound offormula R³⁰ -Hal, where Hal represents halo, such as chloro or bromo, inthe presence of a base.

Suitable bases of use in the reaction include tertiary amines such as,for example, triethylamine.

The reaction is conveniently effected in a suitable organic solvent,such as an ether, for example diethyl ether.

Intermediates of formula (IV) may be prepared by reaction of compoundsof formula (V) with compounds of formula (VI) ##STR8## wherein R², R³,R⁴, R⁵, Z, m and Hal are as previously defined.

The reaction is conveniently effected in a suitable organic solvent,such as an ether, for example diethyl ether.

Compounds of formula (V) may be Prepared by reaction of a compound offormula (VII), or an appropriately protected derivative thereof, with acompound of formula (VIII) ##STR9##

Wherein R² R³ and R⁴ are as previously defined, one of R⁴⁰ and R⁴¹represents ZH where Z is as previously defined and the other of R⁴⁰ andR⁴¹ represents a leaving group, in the presence of a base, followed bydeprotection, if required.

Suitably R⁴⁰ represents ZH and R⁴¹ represents a leaving group.

Suitable leaving groups include halo, e.g. chloro, bromo or iodo, orsulphonate derivatives such as tosylate or mesylate.

The reaction is conveniently carried out in a suitable organic solvent,such as dimethylformamide, at a temperature in the region of 0° C.Favoured bases of use in the reaction include alkali metal hydrides,such as sodium hydride.

The intermediates of formula (VII) above wherein R⁴⁰ is SH may beprepared from the corresponding intermediates of formula (VII) whereinR⁴⁰ represents OH by treating the latter compound with hydrogen sulphidein the presence of aluminium oxide, as described by Lucien et al.,Nouveau J. Chem., 3, 15 (1979), or phosphorus pentasulphide in asuitable solvent, e.g. pyridine, at ambient or elevated temperatures,suitably at reflux temperature.

Intermediates of formula (VII) wherein R⁴⁰ is a leaving group may beprepared form intermediates of formula (VII) wherein R⁴⁰ represents OHas described for the preparation of compounds of formula (II) fromcompounds of formula (IV) above.

Intermediates of formula (VII) wherein R⁴⁰ is OH are commerciallyavailable or may be prepared from commercially available startingmaterials by conventional procedures which will be readily apparent tothose skilled in the art.

Intermediates of formula (III) may be prepared from compounds of formula(IX) ##STR10## wherein R², R⁴, R⁵, R⁴⁰ and m are as previously definedby reaction with compounds of formula (VIII) as previously defined, inthe presence of a base, as described for the preparation of compounds offormula (V) above.

Compounds of formula (IX) wherein R⁴⁰ is SH or a leaving group may beprepared from compounds of formula (IX) wherein R⁴⁰ is OH analogously tothe preparation of compounds of formula (VII) wherein R⁴⁰ is SH or aleaving group.

Compounds of formula (IX) wherein R⁴ is H and R⁴⁰ is OH may be preparedfrom compounds of formula (X) ##STR11## wherein R², R⁵ and m are aspreviously defined, or alkyl esters thereof, by reduction.

Suitable reducing agents include metal hydrides, such as lithiumaluminium hydride. The reaction is conveniently effected in a suitableorganic solvent such as ether, for example, tetrahydrofuran, suitably atelevated temperature, such as the reflux temperature of the solvent.

Compounds of formula (X) are commercially available or may be preparedby conventional procedures for the preparation of amino acids which arewell documented and are described, for example, in Chemistry andBiochemistry of the Amino Acids, ed. G. C. Barrett, Chapman and Hall,1985.

Compounds of formula (IX) wherein R⁴⁰ is OH and R⁴ is other than H maybe prepared from intermediates of formula (XI) ##STR12## wherein R², R⁵and m are as defined for formula (I), by reaction with an organometallicreagent of formula MR⁴, wherein R⁴ is as previously defined and Mrepresents a metal, such as lithium, or a metal halide, such as amagnesium halide, e.g. magnesium chloride or magnesium bromide.

The reaction is suitably effected in an inert organic solvent such as anether, for example, diethylether or tetrahydrofuran.

Aldehydes of formula (XI) may be prepared by reduction of esters ofcompounds of formula (X) using diisobutylaluminium hydride.

Where the above-described process for the preparation of the compoundsaccording to the invention gives rise to mixtures of stereoisomers theseisomers may, if desired, be separated, suitably by conventionaltechniques such as preparative chromatography.

The novel compounds may be prepared in racemic form, or individualenantiomers may be prepared either by enantiospecific synthesis or byresolution. For example, compounds of formula (I) wherein R¹ is H may beresolved into their component enantiomers by standard techniques, suchas the formation of diastereomeric esters or amides, followed bychromatographic separation and removal of the chiral auxiliary. Thesecompounds-can then be used to make individual enantiomers of compoundsof formula (I) wherein R¹ is other than H.

During any of the above synthetic sequences it may be necessary and/ordesirable to protect sensitive or reactive groups on any of themolecules concerned. This may be achieved by means of conventionalprotecting groups, such as those described in Protective Groups inOrganic Chemistry, ed. J. F. W. McOmie, Plenum Press, 1973; and T. W.Greene and P. G. M. Wutts, Protective Groups in Organic Synthesis, JohnWiley & Sons, 1991. The protecting groups may be removed at a convenientsubsequent stage using methods known from the art.

The following Examples illustrate the preparation of compounds accordingto the invention.

EXAMPLE 1(+)-1[(3,5-Bistrifluoromethylphenyl)methyloxy]-2-N(2,5-dimethylpyrrole)-2-phenyl ethane

a) L-2-Phenylglycinol (5 g) and di-t-butyldicarbonate (9.4 g) wasstirred in a dichloromethane solution (30 ml) at room temperature for 3hours. The precipitate which formed was filtered to giveN-t-butoxycarbonyl-L-2-phenylglycinol, 4 g.

b) To a solution of 2-N-t-butoxycarbonylamino-L-2-phenylglycinol (23.7g; Example 1a) and 3,5-bis(trifluoromethyl)benzyl bromide (33.8 g)dissolved in dimethylformamide (75 ml) was added sodium hydride (80%suspension in oil, 3.3 g) in portions over 30 minutes. After stirringthe solution at ambient temperature for 1 h, water (500 ml) and ethylacetate (500 ml) were added. The organic phase was washed further withwater (2×100 ml), saturated brine and dried (MgSO₄). After evaporationin vacuo the residue was chromatographed on silica (eluting with 5%ethyl acetate in petroleum ether bp 60°-80° C.) to give(S)-1-(3,5-bis(trifluoromethyl)phenyl)methyloxy)-2-N-t-butoxycarbonylamino-2-phenylethane,m.p. 53°-54° C.

c) The product of Example 1b (10 g) was allowed to stand in 250 ml ofdiethyl ether saturated with gaseous HCl. The solvent was removed invacuo and the residue recrystallised from diethyl ether-petroleum etherto give crystalline (+)-2-ammonium-1-(bistrifluoromethylphenyl)methyloxy-2-phenyl ethane,hydrochloride salt.

d) To a solutionof(+)-2-ammonium-1-(bistrifluoromethylphenyl)methyloxy-2-phenyl ethane,hydrochloride salt (1 mmol) and 1.1 equivalents of 2,5-hexanedione in5ml methanol was added potassium hydroxide (1.5 mmol). The reaction wasrefiuxed for 48 h and partitioned between dichloromethane-water. Theorganic phase was separated, dried (MgSO₄), concentrated in vacuo, andpoured through a plug of silica using 5% ethyl acetate-pet. ether aseluent. The flitrate was concentrated to give the title compound as aclear oil: (CDCl₃) δ2.05 (6H, s), 4.1-4.15 (1H, m), 4.4-4.45 (1H, m),4.5-4.7 (2H, m), 5.6-5.65 (1H, m), 5.8 (2H, s), 7.1-7.15 (2H, m),7.2-7.4 (3H, m), 7.7 (2H, s), 7.8 (1H, s); Found: C, 62.43; H, 4.83; N,3.32. C₂₃ H₂₁ NOF₆ requires: C, 62.58; H, 4.79; N, 3.17.

EXAMPLE 2 1-[(3,5-Bistrifluoromethylphenyl)methyloxy]2-N(imidazole)-2-phenyl ethane

a) To a stirred solution of solketal (0.151 mol) in DMF/THF (1:1, 300ml) under a nitrogen atmosphere was added sodium hydride (1.2equivalents of an 80% dispersion in mineral oil). The anion was allowedto form over one hour prior to addition of 3,5-bistrifluoromethylbenzylbromide. The reaction was partitioned between ethyl acetate-saturatedammonium chloride after 1 h and the organic phase separated, dried(MgSO₄), and concentrated to a yellow oil. Chromatography using pet.ether then 20% ethyl acetate-pet. ether as eluent gave 2,2-dimethyl-1,3-dioxolane-4-methanol-3,5-bistrifluoromethylbenzyl ether as a yellowoil: (CDCl₃) δ1.4 (3H, s), 1.45 (3H, s), 3.6-3.65 (2H, m), 3.7-3.8 (1H,m), 4.1-4.15 (1H, m), 4.3-4.4 (1H, m), 4.7 (2H, s), 7.8 (3H, s).

b) The product from a) above was dissolved in 150 ml THF and allowed tostand for 18 h with 30 ml 2N hydrochloric acid. THF was removed in vacuoand the residue partitioned between ethyl acetate and saturated sodiumcarbonate solution. The organic phase was separated, dried (MgSO₄) andconcentrated to give 1-glyeerol-(3,5-bistrifluorobenzyl)ether as ayellow oil: (CDCl₃) δ2.0 (1H, s), 2.6 (1H, s), 3.6-3.7 (3H, m), 3.7-3.8(1H, m), 3.9-4.0 (1H, m), 4.7 (2H, s), 7.8 (2H, s), 7.85 (1H, s).

c) A solution of the diol from b) above in 200 ml dichloromethane wascooled in an ice-water bath, and treated with a solution of 1.1equivalents sodium metaperiodate in 100 ml water. A further 1 g ofsodium metaperiodate was added after 3 h. The reaction was allowed tostand for 48 h, the dichloromethane layer separated, dried (MgSO₄),concentrated in vacuo and purified by chromatography using 20% ethylacetate-pet. ether as eluent, to give[(3,5-bistrifluoromethylphenyl)methyloxy]ethanol as a clear oil. Bp. 94°C./1.31 mBar.

d) To a stirred solution of the aidehyde (3.3 mmol) from c) above in 5ml anhydrous diethyl ether under a nitrogen atmosphere was addedphenylmagnesium bromide (3.0M solution in diethyl ether, 1.3 ml). Thereaction was partitioned between ethyl acetate-saturated ammoniumchloride after 2 h. The organic phase was separated, dried (MgSO₄),concentrated and chromatographed using 20% ethyl acetate-pet. ether aseluent, to give1-[(3,5-bistrifluoromethylphenyl)methyloxy]-2-hydroxy-2-phenyl ethane asa clear oil. (CDCl₃) δ3.6-3.8 (2H, m), 4.7 (2H, s), 4.95-5.05 (1H, m),7.2-7.4 (5H, m), 7.7-7.8 (2H, m).

e) A solution of the alcohol (6.9 mmol) from d) above in 5 ml diethylether was treated with triethylamine (1.44 ml) followed bymethanesulphonyl chloride (0.8 ml). The reaction was stirred for 2 hthen partitioned between ethyl acetate-water. The organic phase wasseparated, dried (MgSO₄) and concentrated to a yellow oil. Purificationby chromatography using 10% ethyl acetate-pet. ether as eluent gave themesylate as a pale yellow oil.

f) A mixture of the mesylate (0.7 mmol) from e) above and 1.2equivalents of the sodium salt of imidazole in 4 ml DMF/THF (1:1) wasallowed to stand overnight. The reaction was partitioned between diethylether-water, the organic phase separated, dried (MgSO₄), concentrated invacuo and purified by chromatography using 20% ethyl acetate-pet. etheras eluent to afford the title compound as a clear oil: (CDCl₃) δ4.1-4.15(2H, m), 4.6-4.7 (2H, m), 5.4-5.45 (1H, m), 7.0 (1H, s), 7.1 (1H, s),7.15-7.2 (2H, m), 7.3-7.4 (3H, m), 7.6-7.65 (3H, m), 7.8 (1H, s).

EXAMPLE 3 (±)-1-[(3,5-Bistrifluoromethylphenyl)methyloxy]-2-N(2-nitroimadazole-2-phenylethane

A suspension of 2-nitroimidazole (2.5 mmol) in 3 ml anhydrous THF wasstirred under nitrogen and treated with sodium hydride (1.1 equivalentsof an 80% dispersion in oil). The anion was allowed to form over 2 hprior to being reacted in an analogous manner described in Example 2 togive the title compound as a yellow oil. (CDCl₃) δ4.1-4.2 (2H, m),4.6-4.8 (2H, m), 6.5-6.6 (1H, m), 7.1-7.4 (7H, m), 7.6 (2H, s), 7.8 (1H,s)

EXAMPLE 4 (±)-2N(2-aminoimidazole)-1[(3,5-bistrifluoromethylphenyl)methyloxy)]-2-phenyl ethane

1-[(3,5-bistrifluoromethylphenyl)methyloxy]-2-N(2-nitroimidazole)-2-phenyl ethane (Example 3) (60 mg) was dissolved in 10 mlmethanol and was hydrogenolysed over 100 mg Pd/C at 50 psi for 3 h. Thecatalyst was removed by filtration, the filtrate concentrated in vacuoand purified by chromatography using methanol-ethyl acetate as eluent,to give the title compound as an oil. (CDCl₃) δ4.0-4.2 (4H, m), 4.6-4.7(2H, m), 5.3-5.4 (1H, m), 6.6-6.7 (2H, m), 7.2-7.4 (5H, m), 7.7 (2H, s),7.8 (1H, s).

EXAMPLE 5(±)-1-[(3,5-Bistrifluoromethylphenyl)methyloxy]-2-N(4-nitroimidazole)-2-phenylethane

The title compound was prepared in an analogous manner to that describedin Example 3 using 4-nitroimidazole (6.6 mmol): (CDCl₃) δ4.1-4.2 (2H,m), 4.7 (2H, s), 5.2-5.3 (1H, m), 7.2-7.3 (2H, m), 7.4-7.45 (3H, m),7.55 (1H, s), 7.6 (2H, s), 7.8 (2H, 2).

EXAMPLE 6(±)-1-[(3,5-Bistrifluoromethylphenyl)methyloxy]-2-N-morpholino-2-phenylethane hydrochloride salt

A solution of 2,5-dihydrofuran (0.11 ml) in methanol (10 ml) was cooledto -78° C. Ozone gas was bubbled through the solution until a bluecolouration developed. The mixture was flushed with nitrogen and thensodium cyanoborohydride (0.22 g) was added. After stirring at -78° C.for 10 minutes, a solution of1-[3,5-bistrifluoromethylphenyl)methyloxy-2-amino-2-phenyl ethane inmethanol (8 ml) was added dropwise and the reaction mixture stirred at0° C. for 3 h. The reaction was quenched by addition of acetic acid, andsolvent was removed in vacuo. 10% Sodium hydroxide solution was added tothe residue and the product extracted into dichloromethane (×3). Thecombined organics were washed with brine, dried (MgSO₄) and concentratedin vacuo. The product was purified by chromatography on silica using20%→30%→40% ethyl acetate in petrol as eluent. The product was dissolvedin diethyl ether and a methanolic solution of hydrogen chloride wasadded. Solvent was removed in vacuo and the title comnound obtained bytrituration with diethyl ether. MS (CI⁺) m/z 434 ((M+1)⁺ 100%).

EXAMPLE 7(±)-1-[(3,5-Bitrifluoromethylphenyl)methyloxy]-2-N-(piperidine-2,6-dione-2-phenylethane

A solution of 1-[3,5-bistrifluoromethylphenyl)methyloxy-2-amino-2-phenylethane (0.28 g) in toluene (5 ml) was added to a solution of glutaricanhydride (0.088 g) in toluene (10 ml) and the reaction mixture heatedat reflux for 20 h. Solvent was removed in vacuo and the crude materialpurified by chromatography on silica using 15% ethyl acetate in petrolas eluent. The title compound was recrystallised from ethylacetate-petrol. MS (CI⁺) m/z 460 ((M+1)⁺ 80% ).

We claim:
 1. A compound of formula (I), or a pharmaceutically acceptablesalt or prodrug thereof: ##STR13## wherein R¹ is imidazoyl nitro, NR^(a)R^(b) and NR^(a) COR^(b), where R^(a) and R^(b) each independentlyrepresent H, C₁₋₆ alkyl or phenyl optionally substituted by C₁₋₆ alkyl,halo or trifluoromethyl;R² represents H, C₁₋₆ alkyl or C₂₋₆ alkenyl; R³represents C₁₋₃ alkyl substituted by a phenyl group which may itselfoptionally be substituted by one or more of C₁₋₆ alkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, halo, cyano, nitro, trifluoromethyl and trimethylsilyl; R⁴represents H, C₁₋₆ alkyl or C₂₋₆ alkenyl; each R⁵ independentlyrepresents C₁₋₆ alkyl, C₁₋₆ alkoxy, halo or trifluoromethyl; Zrepresents O or S; and m represents 0, 1, 2 or
 3. 2. A compoundaccording to claim 1 wherein R¹ is 5-imidazolyl substituted by a nitroor amino group.
 3. A compound according to claim 1 wherein R² and R⁴ arehydrogen or methyl.
 4. A compound according to claim 1 wherein R³ isC₁₋₃ alkyl substituted by a phenyl group bearing 1 or 2 substituents onthe phenyl ring.
 5. A compound according to claim 4 wherein R³ is methylsubstituted by 3, 5-disubstituted phenyl.
 6. A compound selected from(±) -1- [3,5-(bistrifluoromethylphenyl)methyloxy]-2-N(2-nitroimidazole)-2-phenylethane;(±)-2-N(2-aminoimidazole)-1-[3,5-(bistrifluoromethylphenyl)methyloxy]-2-phenylethane;(±)-1-[3,5-(bistrifluoromethylphenyl)methyloxy]-2-N(4-nitroimidazole)-2-phenylethane;and salts and prodrugs thereof.
 7. A pharmaceutical compositioncomprising one or more compounds of formula (I) as in claim 1 inassociation with a pharmaceutically acceptable carrier.
 8. A method oftreatment of physiological disorder associated with an excess oftachykinin which method comprises administration to a patient in needthereof of a tachykinin reducing amount of a compound of formula (I) ora composition comprising a compound of formula (I) as defined in any oneof claims 1, 4, 6 or 7.